1. Optimal Upstream Therapy: Low Molecular Weight Heparin with GP IIb-IIIa Antagonists
Neal Kleiman
Director Cardiac Catheterization Laboratory
Methodist DeBakey Heart Center
Professor of Medicine
Weill Medical College of Cornell University

2. Neal S. Kleiman, MD DISCLOSURES Grants/Contracted Research
Bristol-Myers Squibb, Sanofi-Aventis U.S. LLC, Schering-Plough Corp./ Merck & Co., Inc.

3. A Two Part Question

4. Part I: What about GP IIb-IIIa Antagonists?
Are they a relic of days gone by: have we gotten so good with modern PCI and front-loading of clopidogrel that we don’t need them anymore?

5. Myocardial (re)Infarction
30-Day Death or
Myocardial (re)Infarction
1.00
Eptifibatide + Enoxaparin (n=380)
Eptifibatide + Heparin (n=366)
0.98
0.96
0.954
Event-free Survival
0.94
Log Rank
p=0.0282
0.92
0.909
0.90 5 10 15 20 25 30
-- Goodman Circulation 2003;107:
Days from Randomization

6. Distribution of Clopidogrel Dosing in Wave 4 (2007)
LD <599 mg
LD >600 mg %
LD <599 mg
LD >600 mg
Any clopid. pre-procedure
Post Procedure only
Chronic Clopid.

7. “Adequate” Clopidogrel Loading by Hospital
WAVE 2
“Adequate” Clopidogrel Loading by Hospital
IQR = 24% - 45%
Median = 32%
Participating Hospitals

8. 96-hour Primary Efficacy Results Prespecified Subgroups
0.7
0.8
0.5
0.6
0.9 1 2
Odds Ratio for Upstream
Eptifibatide (95% CI)
Routine Early
Eptifibatide, %
Delayed
Provisional
9.3
10.0
9.1
9.8
9.7
10.4
8.6
9.5
11.4
10.6
7.7
6.8
8.9
Early Eptifibatide Better
Delayed Provisional Eptifibatide Better
Baseline Characteristic
Overall
Men
Women
Age < 75 yr
Age
>
75 yr
Troponin positive
Troponin negative
Diabetes
No Diabetes
Early clopidogrel intended
No early clopidogrel intended
8.8
10.8
11.5

9. Early ACS: 30-day Death or MI Prespecified Subgroups
0.7
0.8
0.5
0.6
0.9 1 2
Overall
11.2
12.3
Men
11.4
12.0
Women
10.7
13.0
Age < 75 yr
10.2
11.6
14.0
14.6
Troponin positive
Troponin negative
8.1
8.4
Diabetes
11.7
13.8
No Diabetes
10.9
Early clopidogrel intended
10.3
No early clopidogrel intended
13.7
13.4
Baseline Characteristic
Early Eptifibatide Better
Delayed Provisional Eptifibatide Better
Age
>
75 yr
Odds Ratio for Upstream
Eptifibatide (95% CI)
Routine Early
Eptifibatide, %
Delayed
Provisional
21 hours randomization to cath

10. Safety Results (through 120 hours)
Routine Early Eptifibatide (n=4686)
Delayed Provisional Eptifibatide (n=4643)
OR (95% CI) P
Bleeding (all patients, %)
TIMI major ( )
TIMI major or minor ( ) <0.001
GUSTO severe ( )
GUSTO moderate or severe ( ) <0.001
PRBC transfusion ( )
Bleeding (CABG)
Re-operation for bleeding (%) ( )
Chest tube output (mL/24 H)
Thrombocytopenia (<100K, %) ( )
Stroke (total, %) ( )

11. Small Molecule GP IIb/IIIa Inhibition in NSTE ACS
PURSUIT
PRISM
PRISM PLUS
PARAGON B
PARAGON A
Theroux
COMBINED 1998 (n = 23,967)
0.88 ( )
EARLY ACS
ACUITY Timing
EARLY ACS + ACUITY
0.92 ( )
COMBINED 2009 (n = 42,666)
0.89 ( )
0.25
0.50
1.0
2.0
4.0
Odds Ratio for 30-day Death or MI Relative to Control

12. Part II: What About Upstream Use of Low Molecular Weight Heparins?

14. High-Risk ACS Patients
At least 2 of 3 required:
Age  60
ST  (transient) or 
(+) CK-MB or Troponin
Study Design
Randomize (n = 10,000)
Enoxaparin
IV Heparin
60 U/kg  12 U/kg/hr (aPTT sec)
1 mg/kg SC Q12H
Early invasive strategy
Other therapy per AHA/ACC Guidelines
(ASA, -blocker, ACE, clopidogrel, GP IIb/IIIa)
56% GP IIb/IIIa
98% Angiography
48% PCI
Primary endpoint: Death or MI at 30 days 24

15. Death or MI at 30 Days 5 10 15 20 25 30
0.8
0.85
0.9
0.95
1.0
Freedom from Death / MI
Days from Randomization
UFH
Enoxaparin
1.1
HR 0.96 ( )
Caution: 75% of pts received at least one dose of heparin or LMWH prior to randomization

16. PCI Performed within SYNERGY
logit Prob {hcdm30=1}
-2.9
-2.8
-2.7
-2.6
-2.5
-2.4
-2.3
-2.2
-2.1
-2.0
-1.9
-1.8
-1.7
-1.6
-1.5
-1.4
-1.3
-1.2
Time to PCI (Hours) 5 10 15 20 25 30 35 40 45 50
UFH
Enoxaparin
PCI Performed within SYNERGY
9978 Randomized
CABG 1864 (18.7%)
PCI 4687 (47%)
Cons Rx %)
Logit Prob. Death/MI
Enoxaparin 2323
UFH 2364
Stent % %
GP IIb/IIIa % %
Abr V C % %
White AHJ 2006;152:1042

17. Enoxaparin with Thrombolytic Drugs: ExTRACT TIMI 25 Protocol Design
STEMI <6 h Lytic eligible
N= 20,497
Lytic choice by physician (TNK, tPA, rPA, SK)
ASA
Double-blind
Enoxaparin 30 mg IV bolus; SC 1.0 mg/kg q 12 h to hosp. discharge (No IV bolus, 0.75 mg/kg q 12 h if 75 y)
UFH bolus 60 U/kg Infusion 12 U/kg/h for 48 h
Day Primary efficacy endpoint: Death/MI Primary safety endpoint: TIMI major haemorrhage
N=20,479; 17% RRR in Death/MI
Antman EM et al. N Engl J Med 2006;354:

18. EXTRACT: Primary End Point Death or Nonfatal MI (n=20,479)
UFH
12.0%
17% RRR
9.9%
Primary End Point (%)
ENOX
Relative Risk 0.83 (0.77 to 0.90) P<0.0001
The findings for the primary end point are shown here.
Through 30 days Death or nonfatal MI was reduced from 12.0 % in the UFH group to 9.9% in the enoxaparin group.
This 2.1% absolute risk difference corresponded to a 17% RRR with P <
Only 3 of the nearly 21,000 patients were lost to followup !
Lost to follow up = 3
Days
Antman et al N Engl J Med 2006

19. EXTRACT-TIMI 25 PCI Cohort3 6 9 12 15 5 10 20 25 30
Death/MI (%)
Enox. 9.9%
UFH 12.0%
RRR = 17%
p < 0.001
Days
N = 20,479 patients
ExTRACT-TIMI 25
n = 10,256 Enox.
n = 10,223 UFH
~115 hours 3 6 9 12 15 5 10 20 25 30
Death/MI (%)
RRR = 23%
p = 0.001
Days
Enox. 10.7%
UFH 13.8%
n = 2,272 PCI
by 30 days
The primary efficacy end point of this substudy was the composite of all cause mortality or nonfatal recurrent myocardial infarction (MI) through 30 days.
The risk of death or nonfatal recurrent MI was significantly reduced among those patients who underwent PCI by 30 days receiving enoxaparin vs UFH (10.7% vs 13.8%; 0.77 relative risk [RR]; P<0.001). This difference emerged prior to PCI, and then persisted for up to 30 days.
In addition:
ENOX administration was associated with a significantly lower incidence of nonfatal recurrent MI among patients undergoing PCI (7.8% vs 10.9%, ORadj 0.69, 95% CI , p<0.001).
ENOX vs UFH was associated with a 12 hour median delay in the timing of performance of PCI (122 vs 109 hours, p=0.006) and also a reduction in the incidence of PCI (22.8% vs 24.2%, p=0.027).
n = 2,404 PCI
by 30 days
PCI on blinded study drug: N=2,178: Adjusted RRR =34%
~60 hours
Gibson et al: JACC:2007;49:2238 AND Antman EM, et al. NEJM. 2006;354:

20. Reviparin vs UFH in Acute MI: The CREATE Study
HR= 2.49 ( )
20,201 Patients with STEMI
Overall Population
15,570 Randomized
7780 Reviparin
Weight-adjusted:
<50 kg – 50% dose
51-70 kg – 75% dose
7790 Placebo
t-PA or PCI (N=1,062)
Death, MI, CVA, RI
Implications:
PCI-treated pts may benefit from LMWH
With conservative rx, weight adjustment of LMWH may reduce bleeding
Open label heparin for PCI
1 EP : 7 Days

21. Pentasaccharides Fondaparinux (Arixtra® ) Once-a-day Org31550
MOST LIKE NATURAL
Once-a-day
Org31550
MORE POTENT
New binding site discovered
Idraparinux (SanOrg34006)
SIMPLIFIED
Once-a-week
Pentasaccharide have been built to mimic the sequence in heparins, responsible for AT binding.
First step was to copy this sequence as closely as possible
Second was to improve “nature” by adding a sulphoxy at H3.
Third was to make simpler, safer and cheaper alternatives and to further titrate the elimination half-life to once-a-week use.
OCH3
OCH3

22. OASIS-5; Outcomes with Fondaparinux in NSTE ACS
The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators, N Engl J Med 2006;354:

23. PCI Related Complications: Fondaparinux vs Enoxaparin%
The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators, N Engl J Med 2006;354:

24. Conclusions
It depends how you define “upstream” and how you define “low molecular weight heparin”.
If upstream refers to prolonged marination of the patient, the combination looks good, particularly in terms of ischemic events.
The bleeding issue doesn’t look so good until you recognize that fondaparinux is the ultimate low molecular weight heparin.